1. Field of the Invention
The invention relates to a new process for preparing 2-piperazinecarboxamides of the general formula ##STR6## where R.sub.1 is a) unsubstituted or substituted alkyl or b) --OR.sub.4, where R.sub.4 is unsubstituted or substituted alkyl, is alkenyl or aryl, or c) --NR.sub.5 R.sub.6, where R.sub.5 is hydrogen or alkyl and R.sub.6 is alkyl, and R.sub.2 and R.sub.3 are identical or different and are hydrogen, unsubstituted or substituted alkyl, alkenyl or aryl, or the radical of an amino acid or an amino acid ester. The process of the invention enables both the (R) or (S) enantiomers of the 2-piperazinecarboxamides and the mixtures of the enantiomers, e.g., the racemates, to be obtained. The 2-piperazinecarboxamides are, inter alia, important intermediates for preparing orally active HIV-1 protease inhibitors European Published Patent Application No. A 541 168).
2. Background Art
In the previously known synthesis as described in European Published Patent Application No. A 541 168, the N-(t-butyl)-4-(t-butoxycarbonyl)-2(S)-piperazinecarboxamide of the formula ##STR7## is prepared, according to Example 15, starting from the 2-(S)-piperazinecarboxylic acid by conversion into the 1-Z-protected and 4-BOC-protected 2-(S)-piperazine-carboxylic acid by formation of the tert-butylamide and finally by catalytic hydrogenation to remove the Z protective group. This synthesis is very complicated and is therefore only suitable for the laboratory scale. Furthermore, Tetrahedron Letters 1994, 35, 676, discloses the preparation of the compound of the formula Ia in an overall yield of 26% starting from 2-pyrazinecarboxylic acid by further conversion into the t-butylamide, hydrogenation to give the piperazinecarboxamide, racemate resolution using camphorsulphonic acid and finally by introduction of the BOC protective group. This synthesis too is not suitable for transfer to an industrial scale.
3. Broad Description of the Invention
There was therefore the object of developing a synthesis which allows the piperazinecarboxamides to be prepared simply, in good yields and on an industrial scale.
The object was able to be achieved by means of the process of the invention.
The first stage of this process comprises the conversion of a 2-piperazinecarboxylic acid of the formula ##STR8## or a salt thereof into an N-acyl derivative of the general formula ##STR9## where R.sub.1 and R.sub.4 are as defined above.